The Quantum Cliff: A Critical Proton Tunneling Threshold Determines Clinical Severity in RPE65-Mediated Retinal Disease

TL;DR

This study uncovers a quantum-mechanical threshold effect in RPE65 mutations, where proton tunneling influences retinal disease severity, and introduces a new predictive score based on quantum-structural analysis.

Contribution

It demonstrates that quantum proton tunneling governs enzyme activity in RPE65, linking atomic-scale changes to clinical outcomes, and develops a novel quantum-informed predictive metric.

Findings

Mutations reduce proton tunneling probability, affecting enzyme function.

A sharp non-linear 'Quantum Cliff' effect causes drastic activity loss.

The RQAS score distinguishes mild from severe phenotypes effectively.

Abstract

Predicting clinical severity from genotype remains a fundamental challenge in molecular medicine, particularly for enzymes whose function depends on sub-atomic-scale geometry. Mutations in the \textit{RPE65} isomerohydrolase cause Leber Congenital Amaurosis (LCA) and related retinal diseases; however, the kinetic mechanisms connecting sub-atomic-scale perturbations to blindness remain unclear. In this study, we demonstrate that mutations in the human visual isomerase RPE65 are governed by a quantum-mechanical threshold effect arising from proton tunneling in the active site. We established a hybrid quantum-classical structure-to-phenotype pipeline combining AlphaFold structure prediction with \textit{ab initio} quantum simulation using the Variational Quantum Eigensolver (VQE) to analyze minimal proton-coupled electron transfer in the visual cycle. Our analysis reveals that many pathogenic mutations do not merely occlude the active site, but rather strongly reduce the quantum probability of proton tunneling. We observed a sharp non-linear effect, termed the "Quantum Cliff," where minute structural changes (below 0.1 \AA) reduce the reaction rate by multiple orders of magnitude. Based on these findings, we introduce a dimensionless Relative Quantum Activity Score (RQAS) that isolates the geometry-controlled exponential sensitivity of the reaction rate and successfully distinguishes between mild and severe patient phenotypes. These results suggest that RPE65 operates near a quantum-critical point, where sub-Angstrom structural perturbations induce a catastrophic loss of function. Furthermore, our findings establish quantum tunneling as a predictive mechanistic link between atomic structure and clinical phenotype, proposing a general framework for quantum-structural disease modeling.